Cdh17 antibodies and uses thereof

Abstract

The present disclosure provides monoclonal and recombinant anti-CDH17 antibodies (including CDH17 biparatopic and CDH17xCD3 bispecific antibodies and CDH17-binding fragments. Such antibodies and binding fragments are useful for the treatment of cancer, cither alone or in combination with other agents.

What is claimed is: 
     
         1 . An antibody or antigen-binding fragment thereof that has binding specificity to a human Cadherin-17 (CDH17) protein, wherein the antibody or the fragment thereof comprises heavy chain complementarity determining regions (CDR) VH CDR1, VH CDR2, and VH CDR3 and light chain CDRs VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3, respectively, comprise:
 (a) the amino acid sequences of SEQ ID NO: 21-26;   (b) the amino acid sequences of SEQ ID NO: 27-32;   (c) the amino acid sequences of SEQ ID NO: 33-38;   (d) the amino acid sequences of SEQ ID NO: 39-41, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 42;   (e) the amino acid sequences of SEQ ID NO: 43, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 45;   (f) the amino acid sequences of SEQ ID NO: 46-51;   (g) the amino acid sequences of SEQ ID NO: 52-57;   (h) the amino acid sequences of SEQ ID NO: 58-63;   (i) the amino acid sequences of SEQ ID NO: 64-69; or   (j) the amino acid sequences of SEQ ID NO: 70-75.   
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is or comprises a F(ab′) 2 , a F(ab) 2 , a Fab′, a Fab, a Fv, a single chain Fv (scFv), a disulfide stabilized Fv (dsFv), an Fc-scFv, minibody, and a diabody. 
     
     
         3 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 a heavy chain variable region (VH) comprising an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19; and   a light chain variable region (VL) comprising an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20.   
     
     
         4 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein:
 (a) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 2;   (b) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 3, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 4;   (c) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 6;   (d) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8;   (e) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 9, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 10;   (f) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 11, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 12;   (g) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 13, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 14;   (h) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 15, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 16;   (i) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 17, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 18; or   (j) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 19, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 20.   
     
     
         5 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is humanized. 
     
     
         6 . The antibody or antigen-binding fragment thereof of  claim 5 , wherein the VH comprises an amino acid sequence that is at least 90%, at least 95%, or at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 76, 77, 80, 81, 84, 85, and 123; and wherein the VL comprises an amino acid sequence that is at least 90%, at least 95%, or at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 78, 79, 82, 83, 86, 87, and 124. 
     
     
         7 . The antibody or antigen-binding fragment thereof of  claim 6 , wherein the antibody or antigen-binding fragment comprises:
 (a) a variable heavy chain region (VH) comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 76 and a variable light chain region (VL) comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 78;   (b) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 76 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 79;   (c) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 77 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 78;   (d) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 77 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 79;   (e) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 80 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 82;   (f) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO:80 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 83;   (g) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 81 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 82;   (h) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 81 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 83;   (i) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 84 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 86;   (j) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 84 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 87;   (k) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 85 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 86;   (l) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 85 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 87; or   (m) a VH comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 123 and a VL comprising an amino acid sequence having at least 90% identity to an amino acid sequence of SEQ ID NO: 124.   
     
     
         8 . The antibody or antigen-binding fragment thereof of  claim 7 , wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 88, 90, 92, 94, 96, 100, 102, 104, 117, 119, 121, and 125; and   (b) a light chain Fab region comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 89, 91, 93, 95, 97, 101, 118, 103, 105, 120, 122, and 126.   
     
     
         9 . The antibody or antigen-binding fragment thereof of  claim 8 , wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 88, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 89;   (b) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 90, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 91;   (c) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 92, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 93;   (d) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 94, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 95;   (e) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 96, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 97;   (f) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 100, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 101;   (g) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 102, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103;   (h) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 104, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 105;   (i) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 117, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 118;   (j) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 119, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 120;   (k) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 121, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 122; or   (l) a heavy chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 125, and a light chain Fab region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 126.   
     
     
         10 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is conjugated to a drug moiety selected from a cytotoxin, an immunosuppressive agent, a radioisotope, or a toxin. 
     
     
         11 . A biparatopic antibody or antigen-binding fragment thereof comprising a first antigen-binding portion having specificity to a first epitope in human CDH17 and a second antigen-binding portion having specificity to a second distinct non-overlapping epitope within human CDH17, wherein the biparatopic antibody comprises:
 (a) a first antigen binding portion having specificity for an epitope in ECD 3-5 of human CDH17 and a second binding portion having specificity for an epitope in ECD 6-7 of human CDH17; or   (b) a first antigen binding portion having specificity for an epitope in ECD 1-2 of human CDH17 and a second binding portion having specificity for an epitope in ECD 6-7 of human CDH17.   
     
     
         12 . The biparatopic antibody or antigen-binding fragment thereof of  claim 11 , wherein the antibody comprises a first Fab fragment (Arm 1) comprising a first heavy chain variable region and a first light chain variable region and a second Fab fragment (Arm 2) comprising a second heavy chain variable region and a second variable light chain region,
 wherein the first heavy chain variable region, the first light chain variable region, the second heavy chain variable region, and the second variable light chain region, respectively, comprise amino acid sequences that are at least 90% identical to the amino acid sequences of   (a) SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, and SEQ ID NO: 91;   (b) SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 92 and SEQ ID NO: 93;   (c) SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97;   (d) SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, and SEQ ID NO: 120; or   (e) SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 121, and SEQ ID NO: 122.   
     
     
         13 . The biparatopic anti-CDH17 antibody or antigen-binding fragment thereof of  claim 11 , wherein the biparatopic anti-CDH17 antibody or antigen-binding fragment thereof is or comprises a F(ab′) 2 , a F(ab) 2 , IgG-scFv, tandem scFv, or a bispecific antibody. 
     
     
         14 . The biparatopic anti-CDH17 antibody or antigen-binding fragment thereof of  claim 11 , further comprising a drug moiety conjugated to the biparatopic anti-CDH17 antibody or antigen-binding fragment thereof, wherein the drug moiety is selected from a cytotoxin, an immunosuppressive agent, a radioisotope, or a toxin. 
     
     
         15 . A bispecific T cell engager antibody wherein the antibody comprises a first anti-CD3 scFv fragment (Arm 1) and a second Fab fragment (Arm 2) comprising a heavy chain variable region and a light chain variable region specific for CDH17, wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences of:
 (a) SEQ ID NO: 100 and SEQ ID NO: 101;   (b) SEQ ID NO: 102 and SEQ ID NO: 103;   (c) SEQ ID NO: 104 and SEQ ID NO: 105; or   (d) SEQ ID NO: 125 and SEQ ID NO: 126.   
     
     
         16 . The bispecific T cell engager antibody of  claim 15 , wherein the anti-CD3 scFv fragment comprises an amino acid sequence of SEQ ID NO: 98 or SEQ ID NO: 127. 
     
     
         17 . The bispecific T cell engager antibody of  claim 15 , wherein the anti-CD3 scFv fragment, the heavy chain variable region, and the light chain variable region, respectively, comprise the amino acid sequences of:
 (a) SEQ ID NO: 98, SEQ ID NO: 100 and SEQ ID NO: 101;   (b) SEQ ID NO: 98, SEQ ID NO: 102 and SEQ ID NO: 103;   (c) SEQ ID NO: 98, SEQ ID NO: 104 and SEQ ID NO: 105;   (d) SEQ ID NO: 98, SEQ ID NO: 125 and SEQ ID NO: 126; or   (e) SEQ ID NO: 127, SEQ ID NO: 125 and SEQ ID NO: 126.   
     
     
         18 . A bispecific T cell engager antibody wherein the antibody comprises a first anti-CD3 scFv fragment (Arm 1) and a second Fab fragment (Arm 2) comprising a heavy chain variable region and a light chain variable region specific for CDH17, wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences of SEQ ID NO: 125 and SEQ ID NO: 126; and
 wherein the anti-CD3 scFv fragment comprises the amino acid sequence of SEQ ID NO: 98.   
     
     
         19 . A bispecific T cell engager antibody wherein the antibody comprises a first anti-CD3 scFv fragment (Arm 1) and a second Fab fragment (Arm 2) comprising a heavy chain variable region and a light chain variable region specific for CDH17, wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences of SEQ ID NO: 125 and SEQ ID NO: 126; and
 wherein the anti-CD3 scFv fragment comprises the amino acid sequence of SEQ ID NO: 127.   
     
     
         20 . The bispecific T cell engager antibody of  claim 15 , wherein the biparatopic anti-CDH17 antibody or antigen-binding fragment thereof is or comprises a F(ab′) 2 , a F(ab) 2 , IgG-scFv, tandem scFv, and a bispecific antibody. 
     
     
         21 . A nucleic acid encoding the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         22 . An expression vector comprising the nucleic acid of  claim 21 . 
     
     
         23 . A host cell comprising the nucleic acid of  claim 21 . 
     
     
         24 . A pharmaceutical composition comprising a pharmacologically acceptable carrier and the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         25 . A method of treating cancer in a patient in need thereof, comprising administering to the patient the antibody or antigen-binding fragment thereof of  claim 1 .